Process of preparing 10-brominated derivatives of yohimbane alkaloids



United States Patent Ofiice 3,120,535 Patented Feb.4, 1964 The presentinvention relates to a new and novel method of preparing -brominatedderivatives of yohimbane alkaloids having the formula wherein R ishydrogen or methyl and R is hydrogen, keto or hydroxyl.

The compounds of the above formula have significant pharmacologicalactivity and are useful as anti-inflammatory agents, analgesics andtransquilizers. In addition, they are valuable intermediates in theproduction of other compounds of the yohimbane series. The compounds aredescribed and claimed in the application of John Shavel, Jr. andMaximilian von Strandtmann entitled lO-Haloyohimbane Alkaloids andProcess Therefor, filed concurently herewith.

The method of the present invention is adaptable to the preparation ofcompounds bearing the A, B, C, D and E rings as depicted in the abovestructural formula and are, generally, alkaloids of the yohimbaneseries. Depending upon the configuration of the hydrogen atom at the3-position and the existence of cis or transfusion of the D and E rings,four different configurations are possible, that is, yohimbane,3-epiyohimbane, alloyohimban and 3-epialloyohimbane. The presentinvention includes within its scope a method of preparing derivatives ofthese four families of alkaloids bearing bromo, R and R substituents atthe 10, 16 and 17 positions respectively.

We have found that the IO-brominated derivatives having the aboveformula may be prepared in a novel and efficient manner by the reactionof a compound of the formula wherein R and R are as described above withbromine in a solvent system comprising glacial acetic acid and methanol.The reaction goes to completion in a short time at normal ambienttemperatures. The precipitate which forms is collected, and after beingwashed with methanol, is partitioned between chloroform and aqueousammonium hydroxide. The desired IO-bromo compound is recovered from thechloroform extract by evaporation to dryness and is purified bycrystallization.

It has been found that the use of a reaction medium comprising methanolis particularly desirable in facilitating separation and recovery of theproduct. When methanol is not present, purification becomes difiicult.

We have also found that the production of IO-brominated derivativeswherein the R substituent is hydrogen and the R substituent is keto isfacilitated and markedly higher yields are obtained if the keto group ofthe starting material is converted to the corresponding ketal form,having the formula wherein R is lower alkyl, prior to reaction withbromine. Such ketals are conveniently prepared by reaction of the17-keto starting material with a lower aliphatic alcohol of the formulaR OH in an anhydrous acid medium.

The reaction mixture preferably contains a compound effective in takingup the water formed in the reaction, such as acetone dimethyl ketal.

The following examples are included in order further to illustrate thepresent invention:

Example 1 .10-Br0moy0himbane To a solution of 14 g. yohimbane in amixture of ml. glacial acetic acid and 125 ml. methanol is addeddropwise with stirring at room temperature a solution of 8.2 g. brominein 15 ml. glacial acetic acid, the addition taking about 15 minutes forcompletion. After stirring for an additional 15 minutes, the mixture isallowed to stand at room temperature for two hours and the precipitatedsolid is then collected and washed in turn with 30ml. methanol and three30 ml. portions of dry ether. The solid is refluxed with two 50 ml.portions of methanol, collected by filtration while hot, and washed onthe filter with another 50 ml. of hot methanol. The insoluble solid ispartitioned between chloroform and aqueous ammonium hydroxide solution,the aqueous layers are further extracted with chloroform, the combinedchloroform solution is dried over sodium sulfate, and distilled in vacuoto dryness. Refluxing with 50 ml. methanol causes the residue tocrystallize; the hot mixture is filtered and the insoluble crystalsWashed with two 25 ml. portions of hot methanol to yield 7.8 g. ofsolids, M.P. 235240, /a/ 76 (pyridine, c=0.7). A portion isrecrystallize from methanol to give IO-bromoyohimbane, M.P. 236-241",/a/ 73 (pyridine, 0:0.7).

Analysis-Cale: C, 63.51; H, 6.45; N, 7.80; Br, 22.24. Found: C, 63.29;H, 6.55; N, 7.58; Br, 22.53.

Example 2.] O-Bromo-loa-Methylyohimbvne To a solution of 3.1 g.16a-methylyohimbone in a mixture of 25 ml. glacial acetic acid and 50ml. methanol is added dropwise with stirring at room temperature asolution of 1.6 g. bromine in 4 ml. glacial acetic acid, the additiontaking about 15 minutes for completion. After stirring for an additional15 minutes, the mixture is allowed to stand overnight at roomtemperature. The solid which separates is collected and washed on thefilter with 25 ml. methanol. It is then refluxed with 50 ml. methanol,

filtered while hot, and washed on the filter with 10 ml. hot methanol.The insoluble solid is partitioned between chloroform and aqueousammonium hydroxide solution. The chloroform solution is dried oversodium sulfate and distilled in vacuo to dryness. The residue isrecrystallized twice from methanol to give 760 mg. ofl-bromo-16amethylyohimbone, M.P. 276-280, hat/ -6l (pyridine, c=0.67).

Analysis.-Calc.: C, 62.02; H, 5.98; N, 7.23; Br, 20.63. Found: C, 61.70;H, 6.25; N, 7.20; Br, 20.89.

Example 3.--Br0m0-16a-Methyly0himbol To a solution of 15.5 g.l6u-methylyohimbol in a mixture of 125 ml. glacial acetic acid and 125ml. methanol is added dropwise with stirring at room temperature asolution of 8.2 g. bromine in ml. glacial acetic acid, the additiontaking about 15 minutes for completion. After stirring for an additional15 minutes, the mixture is allowed to stand overnight at roomtemperature. The mixture is allowed to evaporate spontaneously (withoutheat) to a volume of 100 ml. and then is treated with 500 ml. absoluteether. The white precipitate which separates from solution is collectedand triturated with two 25 ml. portions of methanol. The insoluble solidis partitioned between chloroform and aqueous ammonium hydroxidesolution. The aqueous layer is further extracted with chloroform, thecombined chloroform layers are dried over sodium sulfate, and distilledin vacuo to dryness. The residue becomes crystalline on trituration with25 ml. acetonitrile. The crystals are collected and recrystallized from50 ml. acetonitrile to give 6.5 g. of crystals, M.P. 227234, /OL/D25 0,(pyridine, c=0.62), /0C/D25 +21 (methanol, c=0.5). Anotherrecrystallization from acetonitrile gives, M.P. 233-237, /lX/ 0,(pyridine, c=0.7), hat/ +21, (methanol, c=0.5).

Analysis-Cale: C, 61.69; H, 6.47; N, 7.20; Br, 20.53. Found: C, 61.36;H, 6.63; N, 7.07; Br, 20.90.

Example 4.-10-Br0m0y0himb0ne Attempts to react yohimbone with bromine bythe procedure of Example 1 result in low yields. Conversion of yohimboneto its dimethyl ketal (17,17-dimethoxyyohimbone) prior to reaction withbromine resulted in a markedly improved yield.

A mixture of 73.5 g. yohimbone, 75 ml. 6 N methanolic hydrogen chloride,100 ml. acetone dimethyl ketal, and 3000 ml. methanol is refluxed untilthe infrared spectrum of a small sample showed complete absence ofcarbonyl absorption; this requires 3-4 hours time. The resultingsolution is distilled at atmospheric pressure to a volume of about 1000ml. and then is allowed to stand overnight at room temperature. Thecrystals which separate are collected and the filtrate is concentratedfurther to obtain additional crops of yohimbone dimethyl ketalhydrochloride. The combined crops are partitioned between aqueousammonium hydroxide and methylene chloride and the methylene chloridesolution is dried over sodium sulfate and distilled in vacuo to drynessto yield an oil. This is refluxed with 250 ml. methanol and allowed tostand at room temperature whereupon 77.6 g. of crystalline yohimbonedimethyl ketal base separates out; M.P. 124-127, /O6/D25 58 (pyridine,0:0.65). The infrared spectrum showed complete absence of carbonyl.

A solution of 34 g. yohimbone dimethyl ketal, prepared as describedabove, in a mixture of 350 ml. glacial acetic acid and 700 ml. methanolis cooled to 40", to -50 and a solution of 17.6 g. bromine in 50 ml.glacial acetic acid is added dropwise with stirring over a period of 20minutes. The reaction mixture is stirred at this temperature for anadditional 30 minutes. To the solution are then added 8 liters absoluteether and the resulting precipitate is collected by filtration; it ispartitioned between chloroform and aqueous ammonium hydroxide and thechloroform solution is distilled in vacuo to dryness. The resulting oilis dissolved in 300 ml. glacial acetic acid and 900 ml. water, and 5 ml.concentrated hydrochloric acid are added. The resulting solution isheated on a steam bath (60) for 10 minutes, cooled, and basified by theaddition of ammonium hydroxide. The resulting precipitate is washed withwater, air-dried and crystallized from methanol to give 16.5 g. of 10-bromoyohimbone, M.P. 298-300", /oc/ 66" (pyridine, 0:0.53).

Almlysis.Calc.: C, 61.13; H, 5.67; N, 7.51; Br, 21.41. Found: C, 61.35;H, 5.83; N, 7.44; Br, 21.50.

In the foregoing examples, all temperatures are given in degreescentigrade.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

A method of preparing a compound of the formula which comprises treatinga compound of the formula References Cited in the tile of this patentUNITED STATES PATENTS Weisenborn Nov. 10, 1959 OTHER REFERENCES Bargeret al.: J our. Chem. Soc. of London, volume 107 (1915), pages 1026 and1027.

Gall et al.: J. Org. Chem, volume 20 (1955), page 1541.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent. No. 3,120,535 February 41 1964 John Shavel, Jr., et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 1, lines 15 to 25, the formula should appear as shown belowinstead of as in the patent:

same column l line 30, for "'transquilizers" read tranquilizers Signedand sealed this 23rd day of June 1964,,

(SEAL) Attest:

EDWARD J, BRENNER Commissioner of Patents ERNEST W, SWIDER AttestingOfficer

